Protection by classical vaccines such as polio vaccine is mediated mostly by neutralizing antibodies, but such antibody-inducing vaccines have been ineffective against viruses causing chronic infection such as HIV or hepatitis C virus. Rather, in this case, T-cell immunity might be crucial as has been confirmed by CD8 cell depletion in AIDS virus infection of macaques (Schmitz, J. E., M. et al., (1999), Science 283:857; and Jin, X., et al., (1999), J. Exp. Med. 189:991her, viral sequences evolving under immune selective pressure would not likely have optimal HLA molecule-binding epitopes. Thus, modifying epitope sequence to improve the CTL response could be one effective strategy toward development of new generations of vaccines (Berzofsky, J. A., et al., (1999) Immunol. Rev. 170:151; and Berzofsky, J. A., et al., (2001) Nature Reviews Immunology 1:209).
CD8 cytotoxic T cells (CTL) play a major role in protection against HIV or SW virus (Musey, L., J. et al., (1997) N Engl J Med 337:1267; Schmitz, J. E., et al., (1999), Science 283:857; and Jin, X., et al., (1999), J. Exp. Med. 189:991.). Nevertheless, the natural immune response to HIV is often unable to clear the infection. Although a number of antigens that induce CTL responses and can help to eliminate or reduce virus production by killing viral producer cells have been reported so far, these do not seem to be sufficient to eliminate infection in most cases. There is no reason to expect that the HIV sequence would have evolved to have optimal CTL epitopes to allow eradication of the virus.
We have previously succeeded in improving the affinity of a hepatitis C core epitope for HLA-A2.1 (Sarobe, P., et al., (1998), J. Clin. Invest. 102:1239) and of a helper epitope for murine class II MHC (Ahlers, J. D., et al., (1997), Proc. Natl. Acad. Sci. U.S.A. 94:10856; and Ahlers, J. D., et al., (2001), J. Clin. Invest. 108:1677), and an epitope-enhanced melanoma peptide has shown efficacy in human clinical trials (Rosenberg, S. A., et al., (1998) Nature Medicine 4:321). Other complementary approaches to improve affinity for T-cell receptors have been devised (Zaremba, S., et al., (1997) Cancer Res 57:4570; and Slansky, J. E., et al., (2000) Immunity 13:529; and Tangri, S., et al., (2001) J Exp Med 194:833). Although one substitution resulting in higher affinity HLA binding of another HIV peptide has been reported (Pogue, R. R., I. et al., (1995) Proc. Natl. Acad. Sci. U.S.A. 92:8166), no systematic attempt to improve epitopes of HIV has been carried out. In particular, no systematic analysis of the competing effects of substitutions on HIV peptide binding to the HLA class I molecule vs peptide/HLA complex binding to the T cell receptor has been reported.
Further, to our knowledge, protection against viral infection in vivo by an epitope-enhanced vaccine mediated by CTL restricted by a human HLA molecule has not previously been demonstrated.